Identification of kidney transplants at elevated risk of acute rejection (AR) and/or chronic injury prior to loss of kidney function (GFR) could guide therapies to prolong graft survival. Because complement activation mediates acute and chronic graft injury and is linked to fibrogenesis, we tested whether measurements of complement and matrix genes were elevated in the urine sediment of recipients who developed AR. We analyzed stored samples from the Clinical Trials in Organ Transplantation 01 study, an observational analysis of blood and urine biomarkers as correlates of AR and GFR in a cohort of 280 unsensitized first kidney transplant recipients followed for 24 mo, outcomes previously reported (Hricik et al AJT 2013). We isolated RNA from serial urine samples collected between 1-24 mo posttransplant from 15 subjects with biopsy-proven AR and from 14 subjects without clinical evidence of AR or subclinical injury on a 6 mo surveillance biopsy. The RNA was analyzed by quantitative PCR for expression of CD3, CXCL9, a panel of complement (including C3, fB) and matrix/tissue remodeling (including ADAM9, EFEMP1, LAMC2 and MMP7) genes. Log(10)-transformed copies of transcripts for CD3 and CXCL9 were >10-fold higher at AR vs controls, confirming previous findings. Copies of transcripts for matrix and tissue remodeling proteins were increased 4-fold (p<0.006) at AR as were C3, C3aR and fB (p<0.05) but not all complement genes. Remarkably, analysis of the serially collected samples revealed 1-2 log higher expression levels of the same genes beginning 1 mo posttransplant to the time of rejection. Therefore differences in gene expression levels between those destined to develop AR and controls were discernable several months prior to the AR episode. In addition to supporting a relationship between complement, fibrogenesis and rejection, these findings indicate that a proinflammatory and profibrogenic profile occurs long before clinically evident injury, and supports the need for additional studies to assess these gene expression profiles in urine as non-invasive biomarkers that predict incipient AR.

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